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STREPTOCOCCAL C5A PEPTIDASE VACCINE STREPTOKOKKEN C5A PEPTIDASE IMPFSTOFF VACCIN a BASE DE PEPTIDASE C5a DU STREPTOCOQUE

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STREPTOCOCCAL C5A PEPTIDASE VACCINE STREPTOKOKKEN C5A PEPTIDASE IMPFSTOFF VACCIN a BASE DE PEPTIDASE C5a DU STREPTOCOQUE Europäisches Patentamt *EP000877624B1* (19) European Patent Office Office européen des brevets (11) EP 0 877 624 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: A61K 39/09 of the grant of the patent: 31.03.2004 Bulletin 2004/14 (86) International application number: PCT/US1997/001056 (21) Application number: 97902076.5 (87) International publication number: (22) Date of filing: 21.01.1997 WO 1997/026008 (24.07.1997 Gazette 1997/32) (54) STREPTOCOCCAL C5A PEPTIDASE VACCINE STREPTOKOKKEN C5A PEPTIDASE IMPFSTOFF VACCIN A BASE DE PEPTIDASE C5a DU STREPTOCOQUE (84) Designated Contracting States: (56) References cited: AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC WO-A-93/14198 WO-A-93/21220 NL PT SE WO-A-95/28960 Designated Extension States: AL LT LV RO SI • THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 265, 1990, pages 3161--3167, XP000653803 (30) Priority: 22.01.1996 US 589756 CHEN C.C. AND CLEARY P.P.: "COMPLETE NUCLEOTIDE SEQUENCE OF THE (43) Date of publication of application: STREPTOCOCCAL C5a PEPTIDASE GENE OF 18.11.1998 Bulletin 1998/47 STREPTOCOCCUS PYOGENES" cited in the application (73) Proprietor: REGENTS OF THE UNIVERSITY OF • THE JOURNAL OF INFECTIOUS DISEASES, vol. MINNESOTA 163, 1991, pages 109-116, XP000653800 Minneapolis MN 55455 (US) O’CONNOR S.P. ET AL: "THE HUMAN ANTIBODY RESPONSE TO STREPTOCOCCAL (72) Inventor: CLEARY, Paul, P. C5a PEPTIDASE" cited in the application Shoreview, MN 55112 (US) • INFECTION AND IMMUNITY, vol. 60, 1992, pages 4239-4244, XP000653845 CLEARY P.P. ET AL.: (74) Representative: Grant, Anne Rosemary "SIMILARITY BETWEEN THE GROUP B AND A Frank B. Dehn & Co. STREPTOCOCCAL C5a PEPTIDASE GENES" 179 Queen Victoria Street cited in the application London EC4V 4EL (GB) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 877 624 B1 Printed by Jouve, 75001 PARIS (FR) EP 0 877 624 B1 Description Background of the Invention 5 [0001] There are several different β-hemolytic streptococcal species that have been identified. Streptococcus pyo- genes, also called group A streptococci, is a common bacterial pathogen of humans. Primarily a disease of children, it causes a variety of infections including pharyngitis, impetigo and sepsis in humans. Subsequent to infection, autoim- mune complications such as rheumatic fever and acute glomerulonephritis can occur in humans. This pathogen also causes severe acute diseases such as scarlet fever, necrotizing fasciitis and toxic shock. 10 [0002] Sore throat caused by group A streptococci, commonly called "strep throat," accounts for at least 16% of all office calls in a general medical practice, depending on the season. Hope-Simpson, E., "Streptococcus pyogenes in the throat: A study in a small population, 1962-1975," J. Hyg. Camb., 87:109-129 (1981). This species is also the cause of the recent resurgence in North America and four other continents of toxic shock associated with necrotizing fasciitis. Stevens, D. L., "Invasive group A streptococcus infections," Clin. Infect. Dis., 14:2-13 (1992). Also implicated in causing 15 strep throat and occasionally in causing toxic shock are groups C and G streptococci. Hope-Simpson, E., "Streptococ- cus pyogenes in the throat: A study in a small population, 1962-1975," J. Hyg. Camb., 87:109-129(1981). [0003] Group B streptococci, also known as Streptococcus agalactiae, are responsible for neonatal sepsis and men- ingitis. T.R. Martin et al., "The effect of type-specific polysaccharide capsule on the clearance of group B streptococci from the lung of infant and adult rats", J. Infect Dis., 165:306-314 (1992). Although frequently a member of vaginal 20 mucosal flora of adult females, from 0.1 to 0.5/1000 newborns develop serious disease following infection during de- livery. In spite of the high mortality from group B streptococcal infections, mechanisms of the pathogenicity are poorly understood. Martin, T. R., et al., "The effect of type-specific polysaccharide capsule on the clearance of Group B strep- tococci from the lung of infant and adult rats," J. Infect. Dis., 165:306-314 (1992). [0004] Streptococcal infections are currently treated by antibiotic therapy. However, 25-30% of those treated have 25 recurrent disease and/or shed the organism in mucosal secretions. At present no means is available to prevent strep- tococcal infections. Historically, streptococcal vaccine development has focused on the bacterium's cell surface M protein. Bessen, D., et al., "Influence of intranasal immunization with synthetic peptides corresponding to conserved epitopes of M protein on mucosal colonization by group A streptococci," Infect. Immun., 56:2666-2672 (1988); Bronze, M. S., et al., "Protective immunity evoked by locally administered group A streptococcal vaccines in mice," Journal of 30 Immunology, 141:2767-2770 (1988). [0005] Two major problems will limit the use, marketing, and possibly FDA approval, of a M protein vaccine. First, more than 80 different M serotypes of S. pyogenes exist and new serotypes continually arise. Fischetti, V. A., "Strep- tococcal M protein: molecular design and biological behavior, Clin. Microbiol. Rev., 2:285-314 (1989). Thus, inoculation with one serotype-specific M protein will not likely be effective in protecting against other M serotypes. The second 35 problem relates to the safety of an M protein vaccine. Several regions of the M protein contain antigenic epitopes which are immunologically cross-reactive with human tissue, particularly heart tissue. The N-termini of M proteins are highly variable in sequence and antigenic specificity. Inclusion of more than 80 different peptides, representing this variable sequence, in a vaccine would be required to achieve broad protection against group A streptococcal infection. New variant M proteins would still continue to arise, requiring ongoing surveillance of streptococcal disease and changes 40 in the vaccine composition. In contrast, the carboxyl-termini of M proteins are conserved in sequence. This region of the M protein, however, contains an amino acid sequence which is immunologically cross-reactive with human heart tissue. This property of M protein is thought to account for heart valve damage associated with rheumatic fever. P. Fenderson et al., "Tropomyosinsharies immunologic epitopes with group A streptococcal M proteins, J. Immunol. 142: 2475-2481 (1989). In an early trial, children who were vaccinated with M protein in 1979 had a ten fold higher incidence 45 of rheumatic fever and associated heart valve damage. Massell, B. F., et al., "Rheumatic fever following streptococcal vaccination, JAMA, 207:1115-1119 (1969). [0006] Other proteins under consideration for vaccine development are the erythrogenic toxins, streptococcal pyro- genic exotoxin A and streptococcal pyrogenic exotoxin B. Lee, P. K., et al., "Quantification and toxicity of group A streptococcal pyrogenic exotoxins in an animal model of toxic shock syndrome-like illness," J. Clin. Microb., 27: 50 1890-1892 (1989). Immunity to these proteins could prevent the deadly symptoms of toxic shock, but will not prevent colonization by streptococci, nor likely lower the incidence of strep throat. Estimates suggest that the incidence of toxic shock infections is 10 to 20 cases per 100,000 population; therefore, use of these proteins to immunize the general population against toxic shock is neither practical nor economically feasible. [0007] Thus, there remains a continuing need for an effective means to prevent or ameliorate streptococcal infections. 55 More specifically, a need exists to develop compositions useful in vaccines to prevent or ameliorate colonization of host tissues by streptococci, thereby reducing the incidence of strep throat and impetigo. Elimination of sequelae such as rheumatic fever, acute glomerulonephritis, sepsis, toxic shock and necrotizing fasciitis would be a direct conse- quence of reducing the incidence of acute infection and carriage of the organism. A need also exists to develop com- 2 EP 0 877 624 B1 positions useful in vaccines to prevent or ameliorate infections caused by all β-hemolytic streptococcal species, namely groups A, B, C and G. Summary of the Invention 5 [0008] The present invention provides a vaccine, and methods of vaccination, effective to prevent or reduce the incidence of β-hemolytic Streptococcus in susceptible mammals, including humans, and domestic animals such as dogs, cows, pigs and horses. The vaccine comprises an immunogenic amount of an enzymatically inactive strepto- coccal C5a peptidase (SCP), or one or more immunogenic fragments or mutants thereof in combination with a phys- 10 iologically-acceptable, non-toxic vehicle. It may also contain an immunological adjuvant. The vaccine can be used to prevent colonization of group A Streptococcus, group B Streptococcus, group C Streptococcus or group G Strepto- coccus. The vaccine may comprise an immunogenic recombinant enzymatically inactive streptococcal C5a peptidase conjugated or linked to an immunogenic peptide or to an immunogenic polysaccharide. [0009] The streptococcal C5a peptidase vaccine can be administered by subcutaneous or intramuscular injection. 15 Alternatively, the vaccine can be administered by oral ingestion or intranasal inoculation. [0010] As described in the working examples below, an SCP gene (scpA49) was cloned into an E. coli expression vector (pGEX-4T-1). The transferase-SCP fusion from the E. coli clone was expressed and purified. The purified re- combinant SCP was then used to immunize mice. The vaccinated mice and a control group of mice were then chal- lenged with wild-type Streptococci. The mice receiving the recombinant SCP vaccine were free of streptococci soon 20 after infection, whereas 30-50% of the control group were culture positive for many days.
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